Download Clinical Guidelines on Management of Prolonged Seizures, Serial

Clinical Guidelines on Management of Prolonged Seizures,
Serial Seizures and Convulsive Status Epilepticus in
Children
HK J Paediatr (New Series) 2010;15:52-63
L Ma, a Yung, e Yau, k Kwong
Foreword
The publication is a project carried out under Hospital Authority Paediatric Coordinating Committee,
Quality Assurance Subcommittee, Working Group on Guideline and Evidence Based Practice. The present
guideline is endorsed by Paediatric Coordinating Committee.
Definition of level of evidence and grading recommendation is based on SIGN grading scheme.1 This
grading scheme has been widely used and is also recommended by Royal College of Paediatrics and Child
Health.
Key to Evidence Statements and Grades of Recommendations
Levels of evidence
1++ High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs) or RCTs with a
very low risk of bias
1+
Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
1-
Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2++ High quality systematic reviews of case control or cohort studies. High quality case control or cohort
studies with a very low risk of confounding or bias and a high probability that the relationship is
causal
2+
Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate
probability that the relationship is causal
2-
Case control or cohort studies with a high risk of confounding or bias and a significant risk that the
relationship is not causal
3
Non-analytic studies, e.g. case reports, case series
4
Expert opinion
Grades of recommendation
A At least one meta-analysis, systematic review of RCTs, or RCT rated as 1++ and directly applicable to
the target population; or A body of evidence consisting principally of studies rated as 1+, directly
applicable to the target population, and demonstrating overall consistency of results
B A body of evidence including studies rated as 2++, directly applicable to the target population, and
demonstrating overall consistency of results; orExtrapolated evidence from studies rated as 1++ or 1+
C A body of evidence including studies rated as 2+, directly applicable to the target population and
demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++
D Evidence level 3 or 4 or
Extrapolated evidence from studies rated as 2+
Good practice points (GPP)
√ Recommended best practice based on the clinical experience of the guideline development grou
Summary of recommendations
Recommendations
1. Spontaneous cessation of generalised convulsive seizures is unlikely after 5-10 minutes and, therefore,
acute treatment with anticonvulsants should be commenced. (Level 2)
2. Treatment of prolonged (>5 minutes) or serial seizures must be started as soon as possible, preferably
in pre-hospitalisation phase. (Level 1+, recommendation A)
3. Rectal diazepam is safe and effective as first-line treatment of prolonged seizures in community setting
or when intravenous access is not available. (Level 1+, recommendation A)
4. Convulsive status epilepticus (CSE) is conventionally defined as epileptic activity persisting for 30
minutes, manifesting in a wide spectrum of clinical symptoms. Children who fail to respond to initial
emergency medication should be managed according to CSE protocol. Treatment should be started
without waiting till seizures last beyond 30 minutes. (GPP)
5. All units admitting children with CSE are recommended to have a protocol for management of CSE with
a clear structured time frame. (GPP)
6. Cardio-respiratory function should be continuously monitored and managed. General emergency
management is essential. Support of cardiovascular function and identification of complications of
prolonged seizures are vital. General measures should be instituted along with drug therapy. (GPP)
7. Intravenous lorazepam or diazepam is indicated for the treatment of initial CSE. (Level 1+,
recommendation A)
8. If benzodiazepines fail to control seizures, intravenous phenytoin (preferred) or phenobarbitone is
indicated. (Level 1++, recommendation B)
9. A trial of intravenous pyridoxine should be given to children under 3 years of age with a prior history of
chronic active epilepsy or SE of unclear aetiology. (GPP)
10 Investigation into the cause of SE should be carried out without delaying initial treatment. The prompt
identification and treatment of the cause of SE are important (GPP):

Antiepileptic drug levels should be checked for a child with epilepsy receiving treatment. (Level
2+, recommendation C)

Electroencephalogram is advisable to confirm diagnosis and monitor treatment response. (Level
3, recommendation D)

Neuroimaging and/or lumbar puncture may be considered if there is no contraindication. (Level 3,
recommendation D)
11. Refractory SE is defined as failure to respond to 2 or 3 antiepileptic drugs in combination with seizure
duration of at least 60 minutes. Patient should be managed in the intensive care unit. Metabolic
disturbances should be monitored closely and corrected. (GPP)
12. General anaesthesia should be instituted for refractory SE as soon as possible. (GPP)
13. EEG monitoring is required when managing refractory SE. (Level 3, recommendation D)
14. Midazolam, propofol and pentobarbitone are the drugs of choice in controlling refractory SE. (Level 3,
recommendation D)
15. Intravenous sodium valproate can be an alternative to diazepam infusion in refractory SE. (Level 1-,
recommendation B)
16. CSE has a high risk of relapse. Antiepileptic drugs that can be titrated quickly to therapeutic range can
be added to optimise seizure control. (Level 2+, recommendation C)
Introduction
Convulsive status epilepticus (CSE) is a life threatening emergency associated with serious mortality and
morbidity. Incidence in developed countries is between 17-23/100,000 with a higher rate in younger
children.2 Outcome of status epilepticus (SE) is determined by its underlying aetiology and duration.
Current mortality estimates ranges from 3 to 9%.2-4 Neurological sequelae of CSE occurred in 6% of those
older than 3 years but rose to 29% of those aged less than 1 year.4 Acute mortality is often related to
systemic disturbances of prolonged seizures. In addition, the longer the seizure lasts, the more difficult it
is to terminate. Rapid and aggressive treatment is required to prevent neuronal damage, systemic
complications and death. Standardised guidelines are believed to improve the quality of emergency care
and outcome.5 For practical purpose, the approach to a child who presented with a tonic-clonic seizure
lasting for more than 5 minutes should be the same as a child with "established status" with the aim to
stop the seizure early and prevent the development of status epilepticus.6
Definitions
The Commission on Classification and Terminology of International League Against Epilepsy (ILAE) defines
SE as "a seizure [that] persists for a sufficient length of time or is repeated frequently enough that
recovery between attacks does not occur".7 Experimental studies have shown that irreversible neuronal
damage was observed after 30 minutes of continuing epileptic activity.8 Therefore, CSE is conventionally
defined as epileptic activity persisting for 30 minutes, manifesting in a wide spectrum of clinical
symptoms.9,10
Prolonged seizure is defined as a seizure lasting longer than 5 minutes but less than 30 minutes. 11-13
Children who have prolonged seizure (>5 minutes) or serial seizures (brief, repetitive seizures with
recovery of consciousness between seizures) are more likely to progress to CSE.14,15 (Level 2)
Treatment
Prolonged Seizures/Serial Seizures
Prompt recognition of prolonged seizures and the need to treat cannot be over-emphasised. A common
misconception for treatment interventions labeled "status epilepticus interventions" is that they begin only
after the patient's seizures has reached the time indicated for SE (30 minutes). Clinical data indicate that
spontaneous cessation of generalised convulsive seizures is unlikely after 5 to 10 minutes and progression
to CSE is more likely. Therefore, acute treatment with anticonvulsants should be commenced.12,14,15
(Level 2)
Any patient experiencing a seizure on arriving at hospital can be considered as having a prolonged
seizure. A pre-hospital trial showed that the time from seizure onset to initiation of treatment was
inversely correlated with the percentage of patients who responded to first-line therapy. Patients receiving
first-line therapy within 30 minutes had >80% response rate compared to 75% within 60 minutes and
63% within 90 minutes.16 Early treatment before admission to hospital reduces the length of seizure and
leads to the use of fewer drugs.17 Treatment of prolonged or serial seizures must be started as soon as
possible, preferably in pre-hospitalisation phase.12,13,17,18 (Level 1+, recommendation A)
Management of prolonged seizures and serial seizures are similar. Initial assessment should follow the
ABC principle of resuscitation. High flow oxygen should be given and the blood glucose measured by
finger-prick stick testing. A brief history and clinical examination (including pre-hospital treatment and
assessing whether seizure was genuine) should be undertaken.12,13,18,19 (GPP)
Regarding the use of intravenous benzodiazepines, Alldredge et al published the results of a randomised,
double-blind trial in an out-of-hospital setting comparing lorazepam, diazepam and placebo in 205 adults
with continuous or repeated seizures lasting more than 5 minutes. Both lorazepam and diazepam were
superior to placebo in termination of seizure (59.1%, 42.6% and 21.1% respectively). 17 (Level 1+,
recommendation A) Administration of benzodiazepines compared to placebo did not result in more
complications such as arterial hypotension or respiratory compromise. These side effects occurred in
10.6% of patients treated with lorazepam, 10.3% diazepam and 22.5% given placebo.17 (Level 1+)
Rectal diazepam is safe and effective as first-line treatment of prolonged seizures in community setting or
when intravenous access is not available.20,21 (Level 1+, recommendation A) Rectal lorazepam may be
more effective than rectal diazepam.22 Rectal administration may be difficult with wheel-chair users and
larger patients. It can be socially unacceptable and there is increasing concern about risk of sexual abuse
allegation.12,23 Buccal or intranasal midazolam is as effective as rectal diazepam and can be considered as
a preferable alternative in community setting.20,23-25 (Level 1+, recommendation A) Buccal use of
midazolam should be used according to an agreed protocol drawn up by specialists and used after
training.13 (GPP) Prolonged seizures should be treated with either nasal or buccal midazolam or rectal
diazepam or rectal lorazepam when intravenous line is not available or in the community setting. (Level
1+, recommendation A) For a small number of children, rectal paraldehyde is more useful.13,26 (Level
2+, recommendation C)
Recommendation Spontaneous cessation of generalised convulsive seizures is unlikely after 5-10
minutes and, therefore, acute treatment with anticonvulsants should be commenced. (Level 2)
Recommendation Treatment of prolonged (>5 minutes) or serial seizures must be started as soon as
possible, preferably in pre-hospitalisation phase. (Level 1+, recommendation A)
Recommendation Rectal diazepam is safe and effective as first-line treatment of prolonged seizures in
community setting or when intravenous access is not available. (Level 1+, recommendation A)
Convulsive Status Epilepticus
Children who fail to respond to initial emergency medication should be managed as CSE. It is not
necessary to wait till seizure lasts beyond 30 minutes.6,12 It has been shown that provision of standardised
guidelines or protocols improve the quality of emergency care and therefore outcome. All units admitting
children with SE should have a protocol for management of convulsive SE with a clear structured time
frame.12,27 (GPP)
For practical purposes and basing on pathophysiological data, CSE is subdivided into stages according to
temporal parameters and responsiveness to antiepileptic drugs. Treatment options are provided
separately for different stages: (1) Initial/early SE (within 20-30 minutes); (2) established SE (30-60
minutes) and (3) refractory SE (>60/90 minutes).18,19,28 There are some key principles of various
treatment guidelines: (1) act upon an agreed treatment protocol, (2) serially provide antiepileptic drugs
quickly and in maximal mg/kg dose, and (3) consider EEG when subtle or non-convulsive SE need to be
excluded.27 Evidence for management of early SE is well supported, whereas evidence for established and
refractory SE is weak.27 The drugs used in children are based largely on adult experience with weight and
age adjustment in doses.12
Recommendation CSE is conventionally defined as epileptic activity persisting for 30 minutes,
manifesting in a wide spectrum of clinical symptoms. Children who fail to respond to initial emergency
medication should be managed according to CSE protocol. Treatment should be started without waiting till
seizures last beyond 30 minutes. (GPP)
Recommendation All units admitting children with SE are recommended to have a protocol for
management of convulsive SE with a clear structured time frame. (GPP)
Initial/early CSE (within 20-30 minutes)
Cardio-respiratory function should be continuously monitored and managed. General emergency
management is essential. Support of cardiovascular function, which is often compromised, is vital.
Systemic complications of prolonged seizures listed in Table 1 should be promptly identified. General
measures should be instituted along with drug therapy. Investigation into the cause of SE must be carried
out without delay of initial treatment.18,19,27,29 (GPP) Core investigations will be further elaborated on
pages 60 and 61.
Veterans Affairs Status Epilepticus Study (VA Status Study) compared intravenous lorazepam,
phenobarbitone, diazepam followed by phenytoin and phenytoin alone in 384 patients who had
generalised convulsive status epilepticus. Better result was observed for lorazapam than phenytoin
alone.30 (Level 1++) Other comparative studies suggested phenytoin, phenobarbitone, diazepam,
lorazepam and midazolam were efficacious in treating initial and established generalised CSE and
benzodiazepines were the first-line drugs.30-33 Intravenous lorazepam or diazepam is indicated for the
treatment of initial CSE. (Level 1+, recommendation A) There is at least one RCT and meta-analysis
showing lorazepam is slightly superior to diazepam.27 Because phenobarbitone had similar efficacy to the
benzodiazepine arms in the VA Status Study, it should also be considered as an appropriate first-line
therapy.30 (Level 1++)
Table 1 Complications of CSE
Cerebral
Hypoxia
Excito-toxic
cerebral
damage
Cerebral oedema and raised intracranial pressure
Cerebral
venous
thrombosis
Infarction
Cardio-respiratory
Hypotension/hypertension
Cardiac
failure
Dysarrhythmia
Respiratory
failure
and
Pulmonary
apnoea
oedema
Aspiration
Metabolic and systemic Hyperpyrexia
Dehydration and electrolyte disturbances
Metabolic acidosis
Acute renal failure
Acute hepatic failure
Rhabdomyolysis
Fractures
Disseminated intravascular coagulopathy
There have been a total of 4 trials, randomised controlled or quasi-randomised controlled trials, providing
evidence-based treatment guidelines in children. Intravenous lorazepam is at least as effective as
intravenous diazepam and is associated with fewer adverse effects. Children receiving diazepam are likely
to require additional antiepileptic drugs to control initial convulsion.22 (Level 1+, recommendation A) In
general, all three benzodiazepines (diazepam, lorazepam and midazolam) are well tolerated, and no clear
superiority in efficacy or effectiveness is shown.11
Treatment with benzodiazepines can be repeated after 5-10 minutes if necessary.6,13,19,27,28,31 In a study of
39 episodes of generalised CSE, 13 episodes responded to intravenous lorazepam after the first
administration and three on the second administration when seizures continued or recurred after 10
minutes, whilst three did not respond. With diazepam, 14 responded to initial administration, two to the
second whilst four did not respond.31 (Level 1+)
Efficacy of rectal paraldehyde in acute seizures was reported in a recent multi-center study. It terminated
convulsion in 62.3% of patients and there was no recorded respiratory depression in any episode. 26 (Level
2+)
Recommendation Cardio-respiratory function should be continuously monitored and managed. General
emergency management is essential. Support of cardiovascular function and identification of complications
of prolonged seizures are vital. General measures should be instituted along with drug therapy. (GPP)
Recommendation Investigation into the cause of SE should be carried out without delaying initial
treatment. The prompt identification and treatment of the cause of SE are important. (GPP)
Recommendation Intravenous lorazepam or diazepam is indicated for the treatment of initial CSE.
(Level 1+, recommendation A)
Established CSE (30-60 minutes)
If benzodiazepines fail to control seizures, intravenous phenytoin (preferred) or phenobarbitone is
indicated.6,18 There have been no data reporting the superiority of one drug over the other. VA Status
Study showed that phenobarbitone was equally efficacious as diazepam plus phenytoin.30 In view that
phenytoin causes less respiratory and central nervous system depression, it is the preferred drug.27
(Level 1++, recommendation B) Phenobarbitone is recommended if patient is already on phenytoin.
Loading dose of phenytoin is 15-20 mg/kg intravenously at a rate not faster than 1 mg/kg/min. Dilution of
phenytoin in glucose solution is to be avoided, because precipitation may occur. A large independent
venous line for infusion is advisable to avoid phlebitis. Heart rate and blood pressure should be closely
monitored. Phenytoin is contraindicated in patients with second-degree heart block or severe hypotension.
Phenytoin may exacerbate cardiotoxicity in toxin-induced seizures, such as in poisoning due to tricyclic
antidepressants. Use of phenytoin in Dravet syndrome should be cautious because of its potential in
seizure exacerbation and induction of involuntary movements. It takes 20-25 minutes to attain its
maximal anti-epileptic effect. Fosphenytoin can be used as an alternative.18
Some studies suggested that sodium valproate might also be a valuable option for established SE. In an
adult randomised study, seizures were aborted in 66% of valproate group and 42% of phenytoin group.
Side effects of the two groups did not differ.34 (Level 1-) Although promising, safety profile for its use in
children remained to be determined especially in view of the risk of unrecognised metabolic disease.
Children under 3 years of age with a prior history of chronic active epilepsy or SE of unclear aetiology
should be given a trial of intravenous pyridoxine to exclude pyridoxine dependent or responsive
seizures.6,19,35,36 (GPP)
Vital status of patient should be continuously monitored and managed. Metabolic disturbances should be
identified and corrected. Admission to intensive care unit should be planned for subsequent treatment.
6,12,18,19
Electroencephalogram (EEG) monitoring to confirm diagnosis and monitor treatment response is
advisable.6,18,19,37 (Level 3, recommendation D) When there is clinical suspicion that neuroimaging
and/or lumbar puncture might be helpful in the management of CSE, they should be done in the absence
of contraindication such as raised intracranial pressure. (Level 3, recommendation D)
Recommendation If benzodiazepines fail to control seizures, intravenous phenytoin (preferred) or
phenobarbitone is indicated. (Level 1++, recommendation B)
Recommendation A trial of intravenous pyridoxine should be given to children under 3 years of age with
a prior history of chronic active epilepsy or SE of unclear aetiology. (GPP)
Refractory SE (>60/90 minutes)
Refractory SE is defined as seizure that fails to respond to two or three antiepileptic drugs in combination
with duration of at least 60 minutes.18,27,38
It is associated with high mortality and morbidity. If initial first and second line antiepileptic agents fail to
control seizure, a paediatric Fellow, preferably a paediatric neurologist, should be informed. Assistance of
an anaesthesiologist or intensivist is advisable. Patient should be managed in the intensive care unit.
Cardio-respiratory and metabolic disturbances should be monitored closely and corrected.6,13,19 (GPP)
There is no study comparing anaesthetic therapy with other anticonvulsants. The decision on further
management is based on retrospective studies and expert opinions.28 There is no recommendation of
which anaesthetic agent should be administered first.18,28
EEG monitoring is required when managing refractory SE.13,18,19,27 (Level 3, recommendation D) In a
study that was conducted in a small group of patients with refractory SE, "EEG suppression pattern"
appeared to be preferable to the "suppression-burst" pattern as the end point of treatment. Nevertheless,
the former is associated with higher risk of hypotension.39 There is no recommendation regarding EEG
end-points.18,40,41
1. Continuous Intravenous Anaesthetic Agents for Refractory SE
Midazolam, propofol and barbiturates are indicated for the treatment of refractory SE only in ICU after
evaluation of potential risks and benefits in individual patients. It has been recommended that when
seizures have been controlled for 12 hours, the drug dosage should be slowly reduced over a further 12
hours. If seizure recurs, the general anaesthetic agent should be given again for 12 hours, and then
withdrawal is attempted again.27
Midazolam
Only one randomised trial is available. An open-label randomised controlled study by Singhi et al including
40 children with refractory SE revealed that seizure activity was controlled in 85.7% of midazolam infusion
group versus 89.5% of diazepam infusion group. The median time to reach seizure control was similar in
both groups. Midazolam was observed to have a higher relapse rate.42 (Level 1-)
Gilbert et al reviewed efficacy of treatment in refractory SE in 111 children from 12 published articles
including case reports, retrospective and prospective studies. Midazolam, pentobarbitone, thiopentone,
isoflurane and diazepam were all effective in seizure control. However, mortality was less frequent in
midazolam treated groups.43 (Level 3, recommendation D)
Igarta et al studied 8 children with refractory SE treated with midazolam bolus followed by infusion, 88%
of cases had seizure terminated at a mean midazolam infusion rate at 14 microgram/kg/min (range 4-24
microgram/kg/min). In the majority of cases, cessation of seizures occurred before achievement of
suppression-burst pattern in EEG. Cardiovascular instability was not associated with midazolam even at
doses resulting in suppression-burst.44 (Level 3, recommendation D)
Morrison et al reported experience of using high-dose midazolam for refractory SE in children. A higher
loading dose (0.5 mg/kg vs 0.15-0.2 mg/kg) led to more rapid seizure control. High infusion rate (mean
10.6 microgram/kg/min, maximum 32 microgram/kg/min) can safely be administered.45 (Level 3,
recommendation D)
Propofol
Propofol acts on location other than the type A receptor of GABA. It has rapid action and is easily
titratable. However, administration of propofol, particularly in children is associated with "Propofol infusion
syndrome" characterised by rhabdomyolysis, cardiac arrhythmia, cardiac failure, metabolic acidosis, renal
failure and death.
A retrospective study of 20 adults with refractory SE treated with propofol and midazolam showed that
seizure control was observed in 64% of propofol group and 67% of midazolam group. Overall mortality
was higher with propofol than midazolam treatment (57% vs 17%).46 (Level 3, recommendation D)
In a retrospective study of refractory SE in children, thiopentone was effective in 55% and propofol 64%
of cases. Propofol was initiated at a bolus of 1-2 mg/kg followed by infusion of 1-2 mg/kg/hour, to a
maximum of 5 mg/kg/hour. Complications, including rhabdomyolysis and hypertriglyceridemia, prompted
discontinuation in 18% of patients.47
Barbituates
Thiopentone (4-8 mg/kg bolus followed by infusion of up to 10 mg/kg/hr) and its metabolite
pentobarbitone (5 mg/kg loading followed by 1-3 mg/kg/hr) have been used for refractory SE in children
and adults. Adequate monitoring including drug level of thiopentone and critical life supports should be
readily available. In a meta-analysis of adult patients with refractory SE, use of pentobarbitone was
associated with less short term treatment failure and less breakthrough seizures but was associated with
more hypotension than midazolam and propofol.48 (Level 3, recommendation D) Studies of
pentobarbitone for refractory SE in children reported an efficacy of 74-100%.43,49,50
Repeated boluses of intravenous phenobarbitone (10 mg/kg) every 30 minutes without reference to a
predetermined maximal serum level or dose has been reported to be effective. A retrospective report of
50 children with refractory SE treated with high-dose phenobarbitone to attain serum level of up to 1481
micromol/L achieved seizure control in 94%. Intubations were common, but hypotension was mild and
unusual.51
Other Anaesthetic Agents
Ketamine, lidocaine and inhaled anaesthetic drugs can be efficacious in some cases of refractory SE.
These drugs should only be administered by physicians experienced in their use and they are only
indicated when other drugs have failed. These drugs should be given only after thorough consideration of
prognostic factors.18,52 (Level 4, recommendation D)
2. Non-anaesthetic Agents for Refractory SE
Sodium Valproate
In an open-label, randomised controlled study of 40 children with refractory SE, 80% of valproate group
and 85% of diazepam group had seizures controlled and the mean time of seizure control was significantly
shorter for valproate than diazepam.53 (5 min vs 17 min) (Level 1-, recommendation B) It may be
particularly useful when successful intubation is unlikely, because there is a lower risk of respiratory
failure than other agents. The initial bolus may be 20-30 mg/kg, periodic dosing (twice per day) may be
appropriate if seizures are terminated. If seizure continues, a continuous infusion of 5 mg/kg/hr may be
effective.51 Data from nine level 3 studies revealed that an inborn error of metabolism was diagnosed in
4.2% of children with SE.37 Valproate should be used with caution in children whose refractory SE is of
unclear aetiology.
Other Non-anaesthetic Agents
Topiramate, levetiracetam, paraldehyde, chlomethiazole infusion, ketogenic diet and epilepsy surgery
have been reported to be effective in some cases of refractory SE.51
Corticosteroids, adrenocorticotropic hormone and plasmapheresis may be useful in the context of
autoimmune aetiologies for refractory SE, such as Rasmussen's encephalitis or vasculitis. Trial of biotin
and folinic acid is worthwhile in intractable status.51
One case series of three children with refractory SE successfully treated with hypothermia along with
barbiturate coma.54 Further data is necessary to determine its benefit.
Recommendation Refractory SE is defined as failure to respond to 2 or 3 antiepileptic drugs in
combination with seizure duration of at least 60 minutes. Patient should be managed in the intensive care
unit. Metabolic disturbances should be monitored closely and corrected. (GPP)
Recommendation General anaesthesia should be instituted for refractory SE as soon as possible. (GPP)
Recommendation
EEG
monitoring
is
required
when
managing
refractory
SE.
(Level
3,
recommendation D)
Recommendation Midazolam, propofol and pentobarbitone are drugs of choice in controlling refractory
SE in children. (Level 3, recommendation D)
Recommendation Intravenous sodium valproate is an alternative to diazepam infusion in refractory SE.
Level 1-, recommendation B)
Further Management of CSE
Sudden withdrawal of anticonvulsants may lead to SE and increased seizure frequency.55 Chronic AED
treatment should be continued during SE.18 (Level 4)
SE may induce cerebral oedema,56 but there are no data demonstrating the benefit of specific antioedema treatment during SE. Specific treatments for cerebral oedema (e.g. mannitol or steroids) are
indicated in selected cases only, depending on patient's clinical condition. These treatments require careful
assessment of potential contraindications.18 (Level 4)
SE is associated with high relapse rate and subsequent seizures.10 Antiepileptic drug is generally required
after resolution of SE to prevent relapses. The choice of different antiepileptic drugs and duration depends
on aetiology, clinical status and individual patient's characteristics.18 (Level 2+, recommendation C)
Recommendation CSE has a high risk of relapse. Antiepileptic drugs that can be titrated quickly to
therapeutic range can be added to optimise seizure control. (Level 2+, recommendation C)
Protocol for in-hospital management and common drugs used in CSE are described in Tables 2 and 3.
Core investigations of Prolonged Seizure/CSE
Antiepileptic drug levels should be considered when a child with treated epilepsy develops SE.37 (Level
2+, recommendation C) Low AED levels were detected in 32% of children on antiepileptic drugs. In one
study it was reported that four of the nine children with low drug levels had the drugs acutely withdrawn
or discontinued within one week.55
The following investigations are indicated for children not known to have epilepsy:37 (Level 3,
recommendation D)









Blood glucose
Blood gas
Urinalysis
Urea and electrolytes
Calcium and magnesium level (for child under 1 year old)
Liver function tests
Plasma ammonia
Complete blood picture
Blood culture
It is also recommended to save 1-2 ml plasma, 1-2 ml serum and 10 ml urine for later analysis.
(*Serum lactate, urine for toxicology if cause of prolonged seizures remained unknown after reviewing the
above core investigations)
Electroencephalogram abnormalities were observed in 43% of children with SE and helped to determine
the nature and location of precipitating electroconvulsive events.37 EEG is also useful in confirming the
diagnosis of SE especially when pseudoseizure is suspected.18,19,29 (Level 3, recommendation D)
Provided that there was no contraindication and no clues to the cause of CSE, neuroimaging and/or
lumbar puncture can be obtained.37 One level 3 study identified bacterial meningitis in 8% of the entire
group of children with CSE and 17% of those with febrile CSE.57 Abnormalities on neuroimaging that may
explain the aetiology of SE were observed in at least 8% of children.37 (Level 3, recommendation D)
Recommendation:

Antiepileptic drug levels should be checked for a child with epilepsy receiving treatment. (Level
2+, recommendation C)

Electroencephalogram is advisable to confirm diagnosis and monitor treatment response (Level
3, recommendation D)

Neuroimaging and/or lumbar puncture may be considered if there is no contraindication (Level
3, recommendation D)
Table 2 Protocol for in-hospital management of CSE
Antiepileptic drug
General
Investigations
measures
Early SE
Airway: oxygen
(within
Cardio-respiratory
20/30 min)
function and
Blood investigations:AED
regular
level (know epilepsy)
monitoring:
Blood glucose, blood gas
ECG,blood
Urinalysis
pressure and
RFT/LFT
SaO2
Calcium and magnesium
Intravenous
level (for child under 1
access Physical
year old)
examination and
Plasma ammonia
history
Complete blood picture
(If pre-hospital benzodiazepine has been
Glucostix
Blood culture
given, early initiation of treatment for
established SE is recommended)
1-2 ml plasma, 1-2 ml
serum and 10 ml urine
saved for later analysis
Established Intravenous* phenytoin (preferred) or / and
Cardio-respiratory Arrange EEG
SE
phenobarbitone (for patients already on
function and
If no contraindication
(30/60
phenytoin)
monitoring
andclinically
Metbolic
indicated:neuroimaging
disturbances
+/- CSF studies
min)
should be
identified and
corrected
Arrange ICU
admission
Intravenous
pyridoxine for
children <3 yr
with unknown
aetioloty
Call paediatric
Fellow
Refractory
Midazolam infusion
ICU care
SE
or
Ventilatory and
EEG monitoring
(>60/90
Thiopentone infusion
haemodynamic
Monitor electrolytes
min)
or
support
andblood gas
Other medications (propofol, valprote, etc.)
Monitor metabolic
can be considered (see text)
disturbances and
systemic
complications
* Intraosseous route if intravenous route cannot be established
Table 3 Common drugs used in CSE
Drug
Dosage
Lorazepam
IVI: 0.1 mg/kg (max 4 mg)
Diazepam
IVI:
0.1-0.3
mg/kg
(max
10
mg)
Rectal: 0.5 mg/kg, 10-20 mg for adult
Midazolam
Buccal:
IVI
infusion:
0.3
0.1-0.5
mg
IVI
bolus
followed
mg/kg
by
continuous
infusion
1-2
microgram/kg/min and increased as needed to 30 microgram/kg/min
Phenytoin
IVI: 15-20 mg/kg not faster than 1 mg/kg/min under cardiac monitor
Phenobarbitone IVI: 15-20 mg/kg at a maximum rate 1 mg/kg/min
High dose phenobarbitone: 10 mg/kg IVI, repeated every 30 min
Thiopentone
IVI: 3-5 mg/kg bolus followed by infusion 3-5mg/kg/hr
Propofol
IVI: bolus of 1-2 mg/kg (max 10 mg/kg) followed by infusion of 1-2 mg/kg/hour, to a
maximum of 5 mg/kg/hour.
Pentobarbitone
IVI: 5 mg/kg loading dose, followed by 1-3 mg/kg/hour
Sodium
IVI: 20-30 mg/kg, periodic dosing (twice per day) may be appropriate if seizures are
valproate
terminated. If seizure continue, a continuous infusion of 5 mg/kg/hr may be effective.
Pyridoxine
IVI: 50-100 mg
Paraldehyde
Rectal, 0.3-0.4 ml/kg, give with same volume of olive oil
Acknowledgement
We thank Pharmacy of Tuen Mun Hospital (represented by Miss YY Lam) on drug advice.
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